Compositions and methods for topical administration

ABSTRACT

Vanishing cream base compositions and vanishing cream compositions suitable for topical application of an active agent to an animal or plant comprising water, at least one alcohol, a polymeric thickening agent, a skin penetration enhancing compound, and an emulsifying agent are provided. Methods for the use and manufacture of such creams are also disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority from U.S. ProvisionalSer. No. 60/480,230, filed Jun. 23, 2003. This application, in itsentirety, is incorporated herein.

The present invention relates generally to compositions foradministration of active agents through the skin and other membranes andmethods of using the same and to methods for administering active agentsusing these compositions.

The present invention relates to compositions effective for the topicaladministration across skin and other membranes of active agents and tothe methods for treating and/or preventing symptoms and/or disordersassociated with disease or hormonal imbalances.

One embodiment of the present invention provides for a vanishing creambase composition suitable for topical application of an active agent toan animal or plant comprising:

-   a. from about 20 to about 70 wt. % water, based on the total weight    of cream base composition;-   b. at least about 10 wt. %, based on the total weight of cream base,    of at least one alcohol;-   c. at least one polymeric thickening agent, optionally having a    nitrogen containing acrylic unit;-   d. a penetration enhancing effective amount of a skin penetration    enhancing compound; and-   e. an emulsifying agent;-   wherein said cream base is stable upon storage at ambient    conditions, and clarifies at a temperature greater than 30° C.

Another embodiment of the present invention provides for a vanishingcream composition suitable for topical application of an active agent toan animal or plant comprising:

-   a. from about 20 to about 70 wt. % water, based on the total weight    of cream base composition;-   b. at least about 10 wt. %, based on the total weight of cream base,    of at least one alcohol;-   c. at least one polymeric thickening agent comprising a nitrogen    containing acrylic unit;-   d. a penetration enhancing effective amount of a skin penetration    enhancing compound;-   e. an emulsifying agent; and-   f. an active agent;-   wherein said cream base is stable upon storage at ambient    conditions, and clarifies at a temperature greater than 30° C.

Another embodiment of the present invention provides a vanishing creambase composition suitable for topical application of a non-ionic activeagent to an animal or plant comprising:

-   a. from about 20 to about 50 wt. % water, based on the total weight    of cream base composition;-   b. at least about 30 wt. %, based on the total weight of cream base,    of at least one alcohol;-   c. at least one polymeric thickening agent comprising a nitrogen    containing acrylic unit;-   d. a penetration enhancing effective amount of a skin penetration    enhancing compound;-   e. an emulsifying agent;-   wherein said cream base is stable upon storage at ambient    conditions, and clarifies at a temperature greater than 30° C.

Another embodiment of the present invention provides a vanishing creambase composition suitable for topical application of an ionic activeagent to an animal or plant comprising:

-   a. at least about 55 wt. % water, based on the total weight of cream    base composition;-   b. at least about 15 wt. %, based on the total weight of cream base,    of at least one alcohol;-   c. at least one polymeric thickening agent comprising a nitrogen    containing acrylic unit;-   d. a penetration enhancing effective amount of a skin penetration    enhancing compound; and-   e. an emulsifying agent;-   wherein said cream base is stable upon storage at ambient    conditions, and clarifies at a temperature greater than 30° C.

Another embodiment of the present invention provides a vanishing creamcomposition suitable for topical application to an animal or plantcomprising:

-   a. from about 20 to about 50 wt. % water, based on the total weight    of cream base composition;-   b. at least about 30 wt. %, based on the total weight of cream base,    of at least one alcohol;-   c. at least one polymeric thickening agent comprising a nitrogen    containing acrylic unit;-   d. a penetration enhancing effective amount of a skin penetration    enhancing compound;-   e. a non-ionic active agent; and-   f. an emulsifying agent;-   wherein said cream base is stable upon storage at ambient    conditions, and clarifies at a temperature greater than 30° C.

Another embodiment of the present invention provides for a vanishingcream composition suitable for topical application of an ionic activeagent to an animal or plant comprising:

-   a. at least about 55 wt. % water, based on the total weight of cream    base composition;-   b. at least about 15 wt. %, based on the total weight of cream base,    of at least one alcohol;-   c. at least one polymeric thickening agent comprising a nitrogen    containing acrylic unit;-   d. a penetration enhancing effective amount of a skin penetration    enhancing compound;-   e. an emulsifying agent; and-   f. an ionic active agent;-   wherein said cream base is stable upon storage at ambient    conditions, and clarifies at a temperature greater than 30° C.

Still another embodiment of the present invention provides a method offorming a vanishing cream suitable for administering a non-ionic activeagent to an animal or plant comprising, mixing:

-   a. from about 20 to about 50 wt. % water, based on the total weight    of cream base composition;-   b. at least about 30 wt. %, based on the total weight of cream base,    of at least one alcohol;-   c. at least one polymeric thickening agent comprising a nitrogen    containing acrylic unit;-   d. a penetration enhancing effective amount of a skin penetration    enhancing compound;-   e. an emulsifying agent; and-   f. a non-ionic active agent.

Another embodiment of the present invention provides a method of forminga vanishing cream suitable for administering a ionic active agent toanimal or plant comprising, mixing:

-   a. from about 20 to about 50 wt. % water, based on the total weight    of cream base composition;-   b. at least about 30 wt. %, based on the total weight of cream base,    of at least one alcohol;-   c. at least one polymeric thickening agent comprising a nitrogen    containing acrylic unit;-   d. a penetration enhancing effective amount of a skin penetration    enhancing compound;-   e. an emulsifying agent; and-   f. an ionic active agent.

Another embodiment of the present invention provides for a vanishingcream composition suitable for topical application to an animalcomprising:

-   a. from about 25 to 50 wt. % water, based on the total weight of    cream base composition;-   b. from about 25 to about 45 wt. %, based on the total weight of    cream base, of at least one alcohol;-   c. at least one polymeric thickening agent comprising a nitrogen    containing acrylic unit;-   d. a penetration enhancing effective amount of a skin penetration    enhancing compound;-   e. an emulsifying agent; and-   f. from about 0.5 wt. % to about 5 wt. % testosterone;-   wherein said cream base is stable upon storage at ambient    conditions, and clarifies at a temperature greater than 30° C.

Another embodiment of the present invention provides a vanishing creamcomposition suitable for topical application to an animal comprising:

-   a. from about 40 to about 50 wt. % water, based on the total weight    of cream base composition;-   b. from about 35 to about 50 wt. %, based on the total weight of    cream base, of at least one alcohol;-   c. at least one polymeric thickening agent comprising a nitrogen    containing acrylic unit;-   d. a penetration enhancing effective amount of a skin penetration    enhancing_ compound;-   e. an emulsifying agent; and-   f. from about 0.5 wt. % to about 5 wt. % prostaglandin E1;-   wherein said cream base is stable upon storage at ambient    conditions, and clarifies at a temperature greater than 30° C.

Another embodiment of the present invention provides a vanishing creamcomposition suitable for topical application to an animal comprising:

-   a. from 0 to about 20 wt. % water, based on the total weight of    cream base composition;-   b. at least 60 wt. %, based on the total weight of cream base, of at    least one alcohol;-   c. at least one polymeric thickening agent comprising a nitrogen    containing acrylic unit;-   d. a penetration enhancing effective amount of a skin penetration    enhancing compound;-   e. an emulsifying agent; and-   f. from about 1 wt. % to about 5 wt. % hydroquinone;-   wherein said cream base is stable upon storage at ambient    conditions, and clarifies at a temperature greater than 30° C.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic representation of the diffusion cells used inExample 1.

FIGS. 2A and 2B show graphs illustrating average flux (FIG. 2A) andcumulative delivery (FIG. 2B) of PGE₁ across human skin vs. time forformulation number 11 in Table 1, against a clear gel control of 1%PGE₁, 5% SEPA-0009, 1% Klucel HF, 65.1% ethanol, and 27.9% water.

FIGS. 3A and 3B show graphs illustrating average flux (FIG. 3A) andcumulative delivery (FIG. 3B) of PGE₁ across human skin vs. time forformulations 11 and 13 in Table 1, against a clear gel control of 1%PGE₁, 5% SEPA-0009, 1% Klucel HF, 65.1% ethanol, and 27.9% water.

FIGS. 4A and 4B show graphs illustrating average flux (FIG. 4A) andcumulative delivery (FIG. 4B) of PGE, across human skin vs. time forformulations 11, 13 and 16 in Table 1, against a clear gel control of 1%PGE1, 5% SEPA-0009, 1% Klucel HF, 65.1% ethanol, and 27.9% water.

1. Active Agents

As used herein, the term “active agent” means any chemical or biologicalmaterial suitable for administration, that produces a desiredbiological, pharmacological, or physiological effect in an animal orplant to which the agent is administered. Such effects may include, butare not limited to (1) having a prophylactic effect on the animal orplant, such as preventing an undesired biological effect, for example,as in preventing an infection; (2) alleviating a condition caused by adisease of the animal or plant, for example, alleviating pain orinflammation caused as a result of disease; and/or (3) eitheralleviating, reducing, or completely eliminating a disease from theanimal or plant. The effect may be local, such as providing for a localanesthetic effect, or it may be systemic. Active agents are present in apharmaceutically effective amount. The term “animal” as use herein isunderstood to also include human beings as well as other mammals.

Active agents that may be used in the compositions of the presentinvention include any locally or systemically active agents which arecompatible with the compositions of the present invention and which canbe delivered through the skin or other membrane to achieve a desiredeffect. In addition to pharmaceuticals, the present invention may alsoinclude other active agents, such as cosmetic agents. Representativeactive agents (grouped by therapeutic class) include but are not limitedto:

Alimentary System

Antidiarrhoeals such as diphenoxylate, loperamide and hyoscyamine.

Cardiovascular System

Antihypertensives such as hydralazine, minoxidil, captopril, enalapril,clonidine, prazosin, debrisoquine, diazoxide, guanethidne, methyldopa,reserpine, trimetaphan.

Calcium channel blockers such as diltiazem, felodopine, amlodipine,nitrendipine, nifedipine and verapamil.

Antiarrhyrthmics such as amiodarone, flecainide, disopyramide,procainamide, mexiletene and quinidine.

Antiangina agents such as glyceryl trinitrate, erythritol tetranitrate,pentaerythritol tetranitrate, mannitol hexanitrate, perhexilene,isosorbide dinitrate and nicorandil.

Beta-adrenergic blocking agents such as alprenolol, atenolol,bupranolol, carteolol, labetalol, metoprolol, nadolol, nadoxolol,oxprenolol, pindolol, propranolol, sotalol, timolol and timolol maleate.

Cardiotonic glycosides such as digoxin and other cardiac glycosides andtheophylline derivatives.

Adrenergic stimulants such as adrenaline, ephedrine, fenoterol,isoprenaline, orciprenaline, rimeterol, salbutamol, salmeterol,terbutaline, dobutamine, phenylephrine, phenylpropanolamine,pseudoephedrine and dopamine.

Vasodilators such as cyclandelate, isoxsuprine, papaverine,dipyrimadole, isosorbide dinitrate, phentolamine, nicotinyl alcohol,co-dergocrine, nicotinic acid, glyceryl trinitrate, pentaerythritoltetranitrate and xanthinol.

Antimigraine preparations such as ergotamine, dihydroergotamine,methysergide, pizotifen and sumatriptan.

Drugs Affecting Blood and Haemopoietic Tissues

Anticoagulants and thrombolytic agents such as warfarin, dicoumarol, lowmolecular weight heparins such as enoxaparin; streptokinase and itsactive derivatives. Haemostatic agents such as aprotinin, tranexamicacid and protamine.

Central Nervous System

Analgesics, antipyretics including the opiod analgesics such asbuprenorphine, dextromoramide, dextropropoxyphene, fentanyl, alfentanil,sufentanil, hydromorphone, methadone, morphine, oxycodone, papaveretum,pentazocine, pethidine, phenoperidine, codeine and dihydrocodeine.Others include acetylsalicylic acid (aspirin), paracetamol, andphenazone.

Hypnotics and sedatives such as the barbiturates, amylobarbitone,butobarbitone and pentobarbitone and other hypnotics and sedatives suchas choral hydrate, chlormethiazole, hydroxyzine and meprobamate.

Antianxiety agents such as the benzodiazepines, alprazolam, bromazepam,chlordiazepoxide, clobazam, chlorazepate, diazepam, flunitrazepam,flurazepam, lorazepam, nitrazepam, oxazepam, temazepam and triazolam.

Neuroleptic and antipsychotic drugs such as the phenothiazines,chlorpromazine, fluphenazine, pericyazine, perphenazine, promazine,thiopropazate, thioridazine and trifluoperazine and the butyrophenone,droperidol and haloperidol and the other antipsychotic drugs such aspimozide, thiothixene and lithium.

Antidepressants such as the tricyclic antidepressants amitryptyline,clomipramine, desipramine, dothiepin, doxepin, imipramine,nortriptyline, opipramol, protriptyline and trimipramine and thetetracyclic antidepressants such as mianserin and the monoamine oxidaseinhibitors such as isocarboxazid, phenelizine, tranylcypromine andmoclobemide and selective serotonin re-uptake inhibitors such asfluoxetine, paroxetine, citalopram, fluvoxamine and sertraline.

CNS stimulants such as caffeine.

Anti-alzheimer's agents such as tacrine.

Antiparkinson agents such as amantadine, benserazide, carbidopa,levodopa, benztropine, biperiden, benzhexol, procyclidine and dopamine-2agonists such asS(−)-2-(N-propyl-N-2-thienylethylamino)-5-hydroxytetralin (N-0923).

Anticonvulsants such as phenytoin, valproic acid, primidone,phenobarbitone, methylphenobarbitone and carbamazepine, ethosuximide,methsuximide, phensuximide, sulthiame and clonazepam.

Antiemetics, antinauseants such as the phenothiazines, prochloperazine,thiethylperazine and 5HT-3 receptor antagonists such as ondansetron andgranisetron and others such as dimenhydrinate, diphenhydramine,metoclopramide, domperidone, hyoscine, hyoscine hydrobromide, hyoscinehydrochloride, clebopride and brompride.

Musculoskeletal System

Non-steroidal anti-inflammatory agents including their racemic mixturesor individual enantiomers where applicable, such as ibuprofen,flurbiprofen, ketoprofen, aclofenac, diclofenac, aloxiprin, aproxen,aspirin, diflunisal, fenoprofen, indomethacin, mefenamic acid, naproxen,phenylbutazone, piroxicam, salicylamide, salicylic acid, sulindac,desoxysulindac, tenoxicam, tramadol and ketoralac. Non-steroidalantiinflammatory agents may also include salicylamide, salicylic acid,flufenisal, salsalate, triethanolamine salicylate, aminopyrine,antipyrine, oxyphenbutazone, apazone, cintazone, flufenamic acid,clonixeril, clonixin, meclofenamic acid, flunixin, coichicine,demecolcine, allopurinol, oxypurinol, benzydamine hydrochloride,dimefadane, indoxole, intrazole, mimbane hydrochloride, paranylenehydrochloride, tetrydamine, benzindopyrine hydrochloide, fluprofen,ibufenac, naproxol, fenbufen, cinchophen, diflumidone sodium, fenamole,flutiazin, metazamide, letimide hydrochloride, nexeridine hydrochloride,octazamide, molinazole, neocinchophen, nimazole, proxazole citrate,tesicam, tesimide, tolmetin, and triflumidate.

Antirheumatoid agents such as penicillamine, aurothioglucose, sodiumaurothiomalate, methotrexate and auranofin.

Muscle relaxants such as baclofen, diazepam, cyclobenzaprinehydrochloride, dantrolene, methocarbamol, orphenadrine and quinine.

Agents used in gout and hyperuricaemia such as allopurinol, colchicine,probenecid and sulphinpyrazone.

Hormones and Steroids

Oestrogens such as oestradiol, oestriol, oestrone, ethinyloestradiol,mestranol, stilboestrol, dienoestrol, epioestriol, estropipate andzeranol.

Progesterone and other progestagens such as allyloestrenol,dydrgesterone, lynoestrenol, norgestrel, norethyndrel, norethisterone,norethisterone acetate, gestodene, levonorgestrel, medroxyprogesteroneand megestrol.

Antiandrogens such as cyproterone acetate and danazol.

Antioestrogens such as tamoxifen and epitiostanol and the aromataseinhibitors, exemestane and 4-hydroxy-androstenedione and itsderivatives. Androgens and anabolic agents such as testosterone,methyltestosterone, clostebol acetate, drostanolone, furazabol,nandrolone oxandrolone, stanozolol, trenbolone acetate,dihydro-testosterone, 17-.alpha.-methyl-19-nortestosterone andfluoxymesterone.

5-alpha reductase inhibitors such as finasteride, turosteride, LY-191704and MK-306.

Corticosteroids such as betamethasone, betamethasone valerate,cortisone, dexamethasone, dexamethasone 21-phosphate, fludrocortisone,flumethasone, fluocinonide, fluocinonide desonide, fluocinolone,fluocinolone acetonide, fluocortolone, halcinonide, halopredone,hydrocortisone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate,hydrocortisone 21-acetate methylprednisolone, prednisolone, prednisolone21-phosphate, prednisone, triamcinolone, triamcinolone acetonide.

Further examples of steroidal antiinflammatory agents includecortodoxone, fluoracetonide, fludrocortisone, difluorsone diacetate,flurandrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and its other esters, chloroprednisone, clorcortelone,descinolone, desonide, dichlorisone, difluprednate, flucloronide,flumethasone, flunisolide, flucortolone, fluoromethalone, fluperolone,fluprednisolone, meprednisone, methylmeprednisolone, paramethasone,cortisone acetate, hydrocortisone, cyclopentylpropionate, cortodoxone,flucetonide, fludrocortisone acetate, flurandrenolone acetonide,medrysone, amcinafal, amcinafide, betamethasone, betamethasone benzoate,chloroprednisone acetate, clocortolone acetate, descinolone acetonide,desoximetasone, dichlorisone acetate, difluprednate, flucloronide,flumethasone pivalate, flunisolide acetate, fluperolone acetate,fluprednisolone valerate, paramethasone acetate, prednisolamate,prednival, triamcinolone hexacetonide, cortivazol, formocortal andnivazol.

Pituitary hormones and their active derivatives or analogs such ascorticotrophin, thyrotropin, follicle stimulating hormone (FSH),luteinising hormone (LH) and gonadotrophin releasing hormone (GnRH).

Hypoglycemic agents such as insulin, chlorpropamide, glibenclamide,gliclazide, glipizide, tolazamide, tolbutamide and metformin.

Thyroid hormones such as calcitonin, thyroxine and liothyronine andantithyroid agents such as carbimazole and propylthiouracil.

Other miscellaneous hormone agents such as octreotide.

Pituitary inhibitors such as bromocriptine.

Ovulation inducers such as clomiphene.

Genitourinary System

Diuretics such as the thiazides, related diuretics and loop diuretics,bendrofluazide, chlorothiazide, chlorthalidone, dopamine,cyclopenthiazide, hydrochlorothiazide, indapamide, mefruside,methycholthiazide, metolazone, quinethazone, bumetanide, ethacrynic acidand frusemide and potassium sparing diuretics, spironolactone, amilorideand triamterene.

Antidiuretics such as desmopressin, lypressin and vasopressin includingtheir active derivatives or analogs.

Obstetric drugs including agents acting on the uterus such asergometrine, oxytocin and gemeprost.

Prostaglandins such as alprostadil (PGE1), prostacyclin (PGI2),dinoprost (prostaglandin F2-alpha) and misoprostol.

Antimicrobials

Antimicrobials including the cephalosporins such as cephalexin,cefoxytin and cephalothin.

Penicillins such as amoxycillin, amoxycillin with clavulanic acid,ampicillin, bacampicillin, benzathine penicillin, benzylpenicillin,carbenicillin, cloxacillin, methicillin, phenethicillin,phenoxymethylpenicillin, flucloxacillin, mezlocillin, piperacillin,ticarcillin and azlocillin.

Tetracyclines such as minocycline, chlortetracycline, tetracycline,demeclocycline, doxycycline, methacycline and oxytetracycline and othertetracycline-type antibiotics.

Aminoglycosides such as amikacin, gentamicin, kanamycin, neomycin,netilmicin and tobramycin. Antifungals such as amorolfine, isoconazole,clotrimazole, econazole, miconazole, nystatin, terbinafine, bifonazole,amphotericin, griseofulvin, ketoconazole, fluconazole and flucytosine,salicylic acid, fezatione, ticlatone, tolnaftate, triacetin, zinc,pyrithione and sodium pyrithione.

Quinolones such as nalidixic acid, cinoxacin, ciprofloxacin, enoxacinand norfloxacin. Sulphonamides such as phthalylsulphthiazole,sulfadoxine, sulphadiazine, sulphamethizole and sulphamethoxazole.

Sulphones such as dapsone.

Other miscellaneous antibiotics such as chloramphenicol, clindamycin,erythromycin, erythromycin ethyl carbonate, erythromycin estolate,erythromycin glucepate, erythromycin ethylsuccinate, erythromycinlactobionate, roxithromycin, lincomycin, natamycin, nitrofurantoin,spectinomycin, vancomycin, aztreonam, colistin IV, metronidazole,tinidazole, fusidic acid and trimethoprim; 2-thiopyridine N-oxide;halogen compounds, particularly iodine and iodine compounds such asiodine-PVP complex and diiodohydroxyquin; hexachlorophene;chlorhexidine; chloroamine compounds; benzoylperoxide.

Antituberculosis drugs such as ethambutol, isoniazid, pyrazinamide,rifampicin and clofazimine. Antimalarials such as primaquine,pyrimethamine, chloroquine, hydroxychloroquine, quinine, mefloquine andhalofantrine.

Antiviral agents such as acyclovir and acyclovir prodrugs, famciclovir,zidovudine, didanosine, stavudine, lamivudine, zalcitabine, saquinavir,indinavir, ritonavir, n-docosanol, tromantadine and idoxuridine.

Anthelmintics such as mebendazole, thiabendazole, niclosamide,praziquantel, pyrantel embonate and diethylcarbamazine.

Cytotoxic agents such as plicamycin, cyclophosphamide, dacarbazine,fluorouracil and its prodrugs [described,for example, in InternationalJournal of Pharmaceutics 111, 223-233 (1994)], methotrexate,procarbazine, 6-mercaptopurine and mucophenolic acid.

Metabolism

Anorectic and weight reducing agents including dexfenfluramine,fenfluramine, diethylpropion, mazindol and phentermine.

Agents used in hypercalcaemia such as calcitriol, dihydrotachysterol andtheir active derivatives or analogs.

Respiratory System

Antitussives such as ethylmorphine, dextromethorphan and pholcodine.

Expectorants such as acetylcysteine, bromhexine, emetine, guaiphenesin,ipecacuanha and saponins.

Decongestants such as phenylephrine, phenylpropanolamine andpseudoephedrine.

Antiasthmatic agents such as terbutaline.

Bronchospasm relaxants such as ephedrine, fenoterol, orciprenaline,rimiterol, salbutamol, sodium cromoglycate, cromoglycic acid and itsprodrugs [described, for example, in International Journal ofPharmaceutics 7, 63-75 (1980)], terbutaline, ipratropium bromide,salmeterol and theophylline and theophylline derivatives.

Allergy and Immune System

Antihistamines such as meclozine, cyclizine, chlorcyclizine,hydroxyzine, brompheniramine, chlorpheniramine, clemastine,cyproheptadine, dexchlorpheniramine, diphenhydramine, diphenylamine,doxylamine, mebhydrolin, pheniramine, tripolidine, azatadine,diphenylpyraline, methdilazine, terfenadine, astemizole, loratidine andcetirizine.

Local anaesthetics such as bupivacaine, amethocaine, lignocaine,cinchocaine, dibucaine, mepivacaine, prilocaine and etidocaine.

Stratum corneum lipids, such as ceramides, cholesterol and free fattyacids, for improved skin barrier repair. See: Man, et al., J. Invest.Dermatol., 106(5), 1096 (1996).

Neuromuscular blocking agents such suxamethonium, alcuronium,pancuronium, atracurium, gallamine, tubocurarine and vecuronium.

Smoking cessation agents such as nicotine, bupropion and ibogaine.

Insecticides and other pesticides which are suitable for local orsystemic application to plants.

Dermatological agents, such as vitamins A and E, vitamin E acetate andvitamin E sorbate.

Allergens for desensitisation such as house dust mite allergen.

Nutritional agents, such as vitamins, essential amino acids andessential fats.

Keratolytics such as the alpha-hydroxy acids, glycollic acid andsalicylic acid.

Psychicenergisers, such as 3-(2-aminopropyl)indole,3-(2-aminobutyl)indole, and the like.

Anti-acne agents such as containing isotretinoin, tretinoin and benzoylperoxide.

Anti-psoriasis agents such as containing etretinate, cyclosporin andcalcipotriol.

Anti-itch agents such as capsaicin and its derivatives such asnonivamide

[Tsai, et al., Drug. Dev. Ind Pharm., 20(4), 719 (1994)].

Anticholinergic agents, which are effective for the inhibition ofaxillary sweating and for the control of prickly heat. Theantiperspirrant activity of agents such as methatropine nitrate,propantheline bromide, scopolamine, methscopolamine bromide, and the newclass of soft antiperspirants, quaternary acyloxymethyl ammonium salts[described, for example, by Bodor, et al., J. Med. Chem. 23, 474 (1980)and also in United Kingdom Specification No. 2010270, published Jun. 27,1979].

Physiologically active peptides and proteins. Specific-examples ofpeptides and proteins include, human growth hormone, LHRH, LHRH analogssuch as goserelin, buserelin, gonadorelin, napharelin and leuprolide,GHRH, GHRF, insulin, insultropin, calcitonin, octreotide, endorphin,TRH, NT-36 (chemical name: [[(s)4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide), liprecin, pituitary hormones (e.g.,HGH, HMG, desmopressin acetate, etc), follicle luteoids, alpha-ANF,growth factors such as growth factor releasing factor (GFRF), beta-MSH,somatostatin, bradykinin, somatotropin, platelet-derived growth factor,asparaginase, bleomycin sulfate, chymopapain cholecystokinin, chorionicgonadotropin, corticotropin (ACTH), erythropoietin, epoprostenol(platelet aggregation inhibitor), glucagon, HCG, hirulog, hyaluronidase,interferon, interleukins, menotropins (urofollitropin (FSH) and LH),oxytocin, streptokinase, tissue plasminogen activator, urokinase,vasopressin, desmopressin, ACTH analogs, ANP, ANP clearance inhibitors,angiotensin II antagonists, antidiuretic hormone agonists, bradykininantagonists, CD4, ceredase, CSI's , enkephalins, FAB fragments, IgEpeptide suppressors, IGF-1, neurotrophic factors, colony stimulatingfactors, parathyroid hormone and agonists, parathyroid hormoneantagonists, prostaglandin antagonists, pentigetide, protein C, proteinS, renin inhibitors, thymosin alpha-1, thrombolytics, TNF, vaccines,vasopressin antagonists analogs, alpha-1 antitrypsin (recombinant), andTGF-beta.

The active agents of the present invention may be either ionic ornon-ionic.

These active agents may be used as such or in the form of salts, estersor prodrugs. Prodrugs include esters, amides, or other derivatives ofactive agents which may generate the active agent in vivo uponadministration. Different drugs may have multiple physiological,pharmacological or cosmetic effects, which, as known to those skilled inthe art, may vary as a function of concentration.

The active agents may be present in the compositions inpharmacologically, pharmaceutically or cosmetically effective amountsand will depend on such factors as the disease or condition beingtreated, the age of the patient and other factors well understood bythose skilled in the art. Generally, amounts of active agent may rangefrom about 0.01 wt. % to about 15 wt. % relative to the weight of thetotal composition, such as from about 0.1 wt. % to about 12% wt, such asfrom about 0.5 wt. % to about 5 wt. %, or from about 1 wt. % to about 10wt. %, or from about 1 wt. % to about 5 wt. %, for example, from about1.5 wt. % to about 3 wt. % by weight of the composition.

2. Cream Base Formulations

The present invention also provides cream base formulations fordelivering one or more active agents to a plant or animal. Such creamcompositions resist separation under ambient conditions, and maintain apleasant consistency for application. Such cream base formulations maydeliver a non-ionic active agent, an ionic active agent, or a mixture ofionic and non-ionic active agents.

Traditionally, cosmetic or pharmaceutical creams were limited tooil-in-water emulsions which contain more than 50 wt. % of water.According to embodiments of the present invention, stable creams mayinclude those with less than 50 wt. % water, by the use of certainpolymeric thickening agents. Such cream formulations have the advantageof being able to incorporate larger quantities of organic solvents, suchas alcohols (e.g., ethanol) while still maintaining acceptable creamproperties. Creams which have, in the past, incorporated skinpenetration enhancing agents have been typically limited to lowconcentrations of these compounds (e.g., <5 wt. %) because higherconcentrations of such skin penetration enhancers resulted in eitheremulsion destabilization, or required more organic solvents, such asalcohols, which will breakdown the cream. Therefore, the creams of thepresent invention provide, inter alia, for creams with higherconcentrations of skin penetration enhancers, while still maintaining anacceptable cream feel.

The term “cream” as used herein refers to a composition which is opaqueor milky at room temperature and is an oil in water emulsion with ahydrophilic phase in which a hydrophobic phase is emulsified anddispersed, in a micellar structure. Cream compositions of the presentinvention may include those cream compositions which clarify or liquefywhen contacted with animal, e.g., human, skin so as to not discolor orotherwise present an unpleasant aesthetic quality to the user. Such“vanishing creams” typically will clarify at temperatures above ambienttemperature, for example, above about 30° C., such as above about 33°C., or above about 35° C. These qualities of a vanishing cream arethought to occur by the thermal breakdown of the micellar structure ofthe cream at elevated temperature, resulting in the separation of theemulsion, and loss of opacity.

The components of the cream base formulations of the present inventionmay include a hydrophobic component, hydrophilic component, and astabilizing effective amount of a polymeric stabilizing agent.Optionally, the cream base formulations may further comprise anemulsifying agent and a skin penetration enhancing agent. The activeagent of the present invention may be dispersed, dissolved or suspendedwithin the cream base formulation of the present invention, for example,in one or both the hydrophobic or hydrophilic components.

a. Hydrophilic Component

Compositions of the present invention include a hydrophilic component,e.g., water and/or other water soluble or water miscible compounds.Suitable water soluble or dispersible ingredients may comprise alcohols,carboxylic acids, diols, triols, polyols and the like.

According to one embodiment of the present invention, the hydrophiliccomponent includes water and one or more alcohols. Suitable alcohols inthe present invention include: straight or branched chain alkyl,aromatic, or alkylene alcohols. In one embodiment, the alcohol used inthe hydrophilic component is a linear alkyl alcohol containing between 1and 6 carbon atoms, for example, methanol, ethanol, n-propanol,iso-propanol, n-butanol, iso-butanol, tert-butanol, 1-pentanol, or1-hexananol. In another embodiment, the alcohol is methanol or ethanol.Polyols, including diols and triols may be present in place of ortogether with the monoalcohol. Representative polyols include, forexample, ethylene glycol, propylene glycol, diethylene glycol, butyleneglycol, and the like. The amount of alcohol used in the hydrophiliccomponent may be selected to accomplish the emulsions described herein,and may generally comprise between 1 and 99 wt. % relative to the totalweight of the hydrophilic component. The alcohol may constitute betweenabout 15 and about 85 wt. % of the hydrophilic component, such asbetween about 30 and about 70 wt. %, for example between about 35 andabout 55 wt. % of the hydrophilic component.

The amount of the hydrophilic component present in the present inventionwill depend on the additional components present in the composition asdescribed herein. The compositions of the present invention will includebetween about 40 and about 90 wt. % relative to the total weight of thehydrophilic component. In one embodiment, the compositions of thepresent invention will include between about 45 and about 85 wt. % ofthe hydrophilic component, such as between about 50 and about 80 wt. %,or between about 60 to about 70 wt. %.

For example, in one embodiment, the hydrophilic phase comprises water inat least about 5 wt. %, for example, at least about 10 wt. %, such atleast about 15 wt. %, at least about 20 wt. %, at least about 25 wt. %,at least about 30 wt. %, at least about 40 wt. %, at least about 45 wt.%, at least about 50 wt. %, at least about 55 wt. %, at least about 60wt. % or least about 70 wt. %, based on the total weight of thecomposition. The amount of water may be less than about 85 wt. % basedon the total weight of the composition, for example, less than about 80wt. %, such as less than about 75 wt. %, less than about 70 wt. %, lessthan about 65 wt. %, less than about 60 wt. %, less than about 50 wt. %,less than about 55 wt. %, less than about 50 wt. %, less than about 45wt. %, less than about 40 wt. % or less than about 35 wt. % water.

The hydrophilic phase may comprise water between about 15 to about 89wt. %, for example, between about 20 and about 80 wt, or from about 25to about 70 wt. %, or from about 30 to about 60 wt. % by weight of thecomposition.

In one embodiment, ethanol may be present in at least 15 wt. % relativeto the total weight of the composition, for example, in at least about20 wt. %, such as at least about 25 wt. %, at least about 30 wt. %, atleast about 40 wt. %, at least about 45 wt. %, at least about 50 wt. %,at least about 55 wt. %, or at least about 60 wt. %. The amount ofethanol may be less than, for example less than about 65 wt. %, such asless than about 60 wt. %, or less than about 55 wt. %, or less thanabout 50 wt. %, or less than about 45 wt. %, or less than about 40 wt.%, or less than about 35 wt. %.

b. Hydrophobic component

The hydrophobic component of the present invention may include an oilyor fatty component, comprising from about 5 to about 60 wt. % of thetotal weight of the composition, for example, from about 9 to about 50wt. % of the total weight of the composition, such as about 12 to about40 wt. % of the total weight of the composition, such as about 15 toabout 30 wt. % of the total weight of the composition.

This fatty component may include one or more oils which may be selectedfrom: volatile or nonvolatile silicones which are linear, branched orcyclic, organomodified or otherwise water-insoluble or fat-soluble,mineral oils such as paraffin oil and liquid petroleum jelly; oils ofanimal origin such as perhydrosqualene; oils of plant origin such assweet almond oil, avocado oil, castor oil, olive oil, jojoba oil, sesameoil, groundnut oil, macadamia oil, grape seed oil, rapeseed oil, copraoil; synthetic oils such as isoparaffins, fluorinated and perfluorinatedoils; and fatty acid esters.

The hydrophobic component may be substantially or essentially waterinsoluble and may be derived from animals, plants, or petroleum and maybe natural or synthetic (i.e., man-made) or semi synthetic.

Non-limiting examples of suitable hydrophobic components include thefollowing representative materials:

-   (1) Mineral oil, also known as petrolatum liquid, a mixture of    liquid hydrocarbons obtained from petroleum. See: The Merck Index,    Tenth Edition, Entry 7048, p. 1033 (1983), and International    Cosmetic Ingredient Dictionary, Fifth Edition, vol. 1, p.415-417    (1993), which are incorporated by reference herein in their    entirety.-   (2) Petrolatum, also known as petroleum jelly, a colloidal system of    branched solid hydrocarbons and high-boiling liquid hydrocarbons, in    which most of the liquid hydrocarbons are believed to be held inside    micelles. See: The Merck Index, Tenth Edition, Entry 7047, p. 1033    (1983); Schindler, Drug. Cosmet. Ind., 89, 36-37, 76, 78-80, 82    (1961); and International Cosmetic Ingredient Dictionary, Fifth    Edition, vol. 1, p. 537 (1993), which are incorporated by reference    herein in their entirety.-   (3) Straight and branched chain hydrocarbons having from about 7 to    about 40 carbon atoms. For example, dodecane, isododecane, squalane,    cholesterol, hydrogenated polyisobutylene, docosane (i.e., a C₂₂    hydrocarbon), hexadecane, isohexadecane (a commercially available    hydrocarbon sold as Permethyl® 101A by Presperse, South Plainfield,    N.J.). Also useful are the C₇-C₄₀ isoparaffins, which are C₇₋₄₀    branched hydrocarbons.-   (4) C₁-C₃₀ alcohol esters of C₁-C₃₀ carboxylic acids and of C₂-C₃₀    dicarboxylic acids, including straight and branched chain materials    as well as aromatic derivatives (as used herein in reference to the    hydrophobic component, mono- and poly-carboxylic acids include    straight chain, branched chain and aryl carboxylic acids).    Non-limiting examples include diisopropyl sebacate, diisopropyl    adipate, isopropyl myristate, isopropyl palmitate, methyl palmitate,    myristyl propionate, 2-ethylhexyl palmitate, isodecyl neopentanoate,    di-2-ethylhexyl maleate, cetyl palmitate, myristyl myristate,    stearyl stearate, isopropyl stearate, methyl stearate, cetyl    stearate, behenyl behenate, dioctyl maleate, dioctyl sebacate,    diisopropyl adipate, cetyl octanoate, diisopropyl dilinoleate.-   (5) mono-, di- and tri-glycerides of C₁-C₃₀ carboxylic acids, e.g.,    caprylic/capric triglyceride, PEG-6 caprylic/capric triglyceride,    PEG-8 caprylic/capric triglyceride.-   (6) alkylene glycol esters of C₁-C₃₀ carboxylic acids, e.g.,    ethylene glycol mono- and di-esters, and propylene glycol mono- and    di-esters of C₁-C₃₀ carboxylic acids e.g., ethylene glycol    distearates.-   (7) propoxylated and ethoxylated derivatives of the foregoing    materials that are substantially hydrophobic.-   (8) C₁-C₃₀ mono- and poly-esters of sugars and related materials.    These esters may be derived from a sugar or polyol moiety and one or    more carboxylic be in either liquid or solid form at room    temperature. Examples of liquid esters include: glucose tetraoleate,    the glucose tetraesters of soybean oil fatty acids, the mannose    tetraesters of mixed soybean oil fatty acids, the galactose    tetraesters of oleic acid, the arabinose tetraesters of linoleic    acid, xylose tetralinoleate, galactose pentaoleate, sorbitol    tetraoleate, the sorbitol hexaesters of unsaturated soybean oil    fatty acids, xylitol pentaoleate, sucrose tetraoleate, sucrose    pentaoleate, sucrose hexaoleate, sucrose hepatoleate, sucrose    octaoleate, and mixtures thereof.-   (9) Organopolysiloxane oils. The organopolysiloxane oil may be    volatile, non-volatile, or a mixture of volatile and non-volatile    silicones. Suitable organopolysiloxanes can be selected from a wide    variety of silicones spanning a broad range of volatilities and    viscosities. Nonlimiting examples of suitable silicones are    disclosed in U.S. Pat. No. 5,069,897, to Orr, issued Dec. 3, 1991,    which is incorporated by reference herein in its entirety. Examples    of suitable organopolysiloxane oils include polyalkylsiloxanes,    cyclic polyalkylsiloxanes, and polyalkylarylsiloxanes.    Organopolysiloxanes may also be selected from polyalkylsiloxanes,    alkyl substituted dimethicones, cyclomethicones,    trimethylsiloxysilicates, dimethiconols, polyalkylaryl siloxanes,    and mixtures thereof. In one embodiment, the polyalkylsiloxanes are    dimethicones.-   (10) Vegetable oils and hydrogenated vegetable oils. Examples of    vegetable oils and hydrogenated vegetable oils include safflower    oil, castor oil, coconut oil, cottonseed oil, menhaden oil, palm    kernel oil, palm oil, peanut oil, soybean oil, rapeseed oil, linseed    oil, rice bran oil, pine oil, sesame oil, sunflower seed oil,    hydrogenated safflower oil, hydrogenated castor oil, hydrogenated    coconut oil, hydrogenated cottonseed oil, hydrogenated menhaden oil,    hydrogenated palm kernel oil, hydrogenated palm oil, hydrogenated    peanut oil, hydrogenated soybean oil, hydrogenated rapeseed oil,    hydrogenated linseed oil, hydrogenated rice bran oil, hydrogenated    sesame oil, hydrogenated sunflower seed oil, and mixtures thereof.-   (11) animal fats and oils, e.g., lanolin and derivatives thereof,    cod liver oil.-   (12) Also useful are C₄-C₂₀ alkyl ethers of polypropylene glycols,    C₁-C₂₀ carboxylic acid esters of polypropylene glycols, and    di-C₈-C₃₀ alkyl ethers. Nonlimiting examples of these materials    include PPG-14 butyl ether, PPG-15 stearyl ether, dioctyl ether,    dodecyl octyl ether, and mixtures thereof.-   (13) The hydrophobic component may also comprise one or more fatty    alcohols, fatty acids or waxes (such as, for example, paraffin,    polyethylene wax, Carnauba wax, beeswax).    c. Polymeric Thickening Agents

Suitable polymeric thickening agents include those polymers thatcomprise a nitrogen containing acrylic unit. Examples of the nitrogencontaining acrylic units include those derived from monomers ofacrylamide, acryloyltaurate, or other arylamides. Examples of polymerscomprising a nitrogen containing acrylic unit include an ionic polyamidepolymer containing acrylamidopropanesulfonic acid (AMPS) and/or itssalts as a comonomer. These polymers can be formed from a variety ofmonomers including acrylamide and methacrylamide, which may beunsubstituted or substituted with one or two alkyl groups (such as C₁ toC₅), or N-vinyl pyrrolidone. In one embodiment the acrylate amide andmethacrylate amide are monomers in which the amide nitrogen isunsubstituted, or substituted with one or two C₁ to C₅ alkyl groups(preferably methyl, ethyl, or propyl), for example, acrylamide,methacrylamide, N-methacrylamide, N-methylmethacrylamide,N,N-dimethylmethacrylamide, N-isopropylacrylamide,N-isopropylmethacrylamide, and N,N-dimethylacrylamide. Specific examplesof the polymeric thickening agents includeacrylamide-acryloyldimethyltaurate or acrylamide-acryloyldimethlaurateor copolymers (e.g., Simulgel 600 available from Seppic, Paris, France),polyacrylamides (e.g., Sepigel 305 available from Seppic, Paris,France), sodium acrylate-sodium acryloyidimethyl laurate or sodiumacrylate-sodium acryloyidimethyl taurate copolymers (e.g.; Simugel EGavailable from Seppic, Paris, France), and ammoniumacryloyidimethyllaurate-Beheneth-25 methacrylate cross polymers (e.g.,Aristoflex available from Clariant Corporation, Charlotte, N.C.).Mixtures of two or more polymeric thickening agents may also be used.

The polymeric thickening agents of the present invention are included inan amount sufficient to prevent visible separation of the compositionfor at least seven days when stored at ambient conditions (i.e., roomtemperature and pressure), after which time, no more than 10% of theactive agent or the optional skin penetration enhancer have degraded, orotherwise reacted. The polymeric thickening agents are generally presentin a concentration of about 0.1 to about 10 wt. %. One of skill in theart will also recognize that the amount of polymeric thickening agentnecessary will depend upon the hydrophobic and hydrophilic phases,intended use, intended storage and use conditions, and other optionalingredients which may be used within the composition as well as themixing conditions and mixing apparatus used to prepare the emulsion ordispersion.

In one embodiment, the polymeric thickening agent is present frombetween about 1 and about 10 wt. % , for example, from about 0.2 toabout 10 wt. %, such as form about 2 to about 10 wt. %, such as fromabout 2 to about 8 wt. %, or from about 3 to about 7 wt. %, such asabout 4 to about 6 wt. %. In another embodiment, the polymericthickening agent is present in an amount of at least about 0.2 wt. %,based on the total weight of the composition, for example, at leastabout 0.5 wt. %, for example, at least about 1 wt. %, at least about 2wt. %, at least about 3 wt. %, at least about 4 wt. %, or at least 5 wt.%.

d. Skin Penetration Enhancing Compounds

In one embodiment a skin penetration enhancing compound is optionallyused to promote permeation of an active agent through the skin. A skinpenetration. enhancing effective amount of the skin penetrationenhancing (SPE) compound may be determined by review of the literaturefor the particular enhancer or otherwise determined by routine in vitroand/or in vivo studies. Skin penetration enhancers containing a C₆ toC₁₂ alkyl group are may be useful in the cream compositions of thepresent invention.

In one embodiment the skin penetration enhancing compound is a2-hydrocarbyl group substituted 1,3-dioxolane of the formula (I):

or a 1,3-dioxane of the formula (II):

or an acetal (including herniacetal) of the formula (III):

where R represents a C₆ to C₂₀ aliphatic group, R₀, R₁, R₂, R₃, R₄, R₅,and R₆, each, independently, represent hydrogen or a C₁ to C₄ aliphaticgroup; R′₁, and R′₂, each, independently, represent C₁ to C₄ aliphaticgroup. Several compounds of these formulas are available commerciallyfrom MacroChem Corporation under the trademark SEPA®.

In one particular embodiment, R represents a C₆ to C₁₂ aliphatic group;especially C₇ to C₁₀ aliphatic group. The aliphatic group may be astraight or branched chain alkyl or alkenyl group, such as, for example,n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,2-methyl-octyl, 4-ethyl-decyl, and the like.

The C₁ to C₄ aliphatic group may be, for example, methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, ethenyl, and the like. In oneembodiment aliphatic groups for R₁ to R₆ and for R′₁ and R′₂ are alkylgroups, especially alkyl having 1 or 2 carbon atoms, most especiallyethyl. R₁ to R₆ may also all be hydrogen.

Specific enhancer compounds (i) include, for example,2-n-heptyl-1,3-dioxolane, 2-n-nonyl-1,3-dioxolane,2-n-undecyl-1,3-dioxolane, 2-n-nonyl-1,3-dioxane,2-n-undecyl-1,3-dioxane, 2-n-heptylaldehyde-acetal,2-n-octyl-aldehyde-acetal, 2-n-nonylaldehyde-acetal,2-n-decylaldehyde-acetal, 3,7-dimethyl-2,6-octadienal (citral), citronaland the like. 2-n-nonyl-1,3-dioxolane (2-NND) is commercially availableas SEPA-0009 from MacroChem Corporation.

Another class of SPE compounds (ii) are cyclic ketones and cycliclactones and derivatives thereof, as disclosed in, for example, U.S.Pat. Nos. 5,023,252 and 5,731,303, the disclosures of which, areincorporated herein, in their entireties, by reference thereto.

The SPE compounds (ii) may be represented by the following formula (IV):

wherein X and Y are oxygen, sulfur or an imino group of the structure

or ═N—R, with the proviso that when Y is the imino group, X is an iminogroup, and when Y is sulfur, X is sulfur or an imino group, A is grouphaving the structure

wherein X and Y are defined above,

-   m and n are integers having a value from 1 to 20 and the sum of m+n    is not greater than 25,-   p is an integer having a value of 0 or 1,-   q is an integer having a value of 0 or 1,-   r is an integer having a value of.0 or 1,-   R represents hydrogen or a straight or branched chain alkyl group    having from 1 to 6 carbon atoms, and,-   R₁, R₂, R₃, R₄, R₅ and R₆, each, independently, represent hydrogen    or a straight or branched chain alkyl group having from 1 to 6    carbon atoms, with the proviso that only one of R₁ to R₆ may be said    alkyl group, and with the further provisos that,-   when p, q and r have a value of 0 and Y is oxygen, m+n is at least    11,-   when X is an imino group, q equals 1, Y is oxygen, and p and r are    0, then m+n is at least 11.

Examples of the alkyl group for R and R₁ to R₆ include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, amyl, hexyl, and thelike.

Preferably, each of R and R₁ to R₆ are hydrogen atoms and X and Y eachrepresent oxygen. These preferred compounds of formula (IV) are,therefore, cyclic ketones (when q and r are each 0) or cyclic lactones.

Another preferred class of compounds of formula (IV) may be representedby the following general formula (IV-A):

wherein X, Y, R, A, m, n, p, q and r, are as defined above.

Preferably, in formula (IV-A), X and Y are each oxygen and R ispreferably hydrogen.

Pentadecalactone is especially preferred as the SPE of type (ii).

Another class of SPE compounds (iii) include analkyl-2-(N,N-disubstituted amino)-alkanoate, an (N,N-disubstitutedamino)-alkanol alkanoate, or a mixture of these, as more fully describedin U.S. Pat. No. 6,046,244, the disclosure of which is incorporatedherein by reference thereto. For convenient reference,alkyl-2-(N,N-disubstituted amino)-alkanoates and (N,N-disubstitutedamino)-alkanol alkanoates can be grouped together under the label alkyl(N,N-disubstituted amino) esters.

Alkyl-2-(N,N-disubstituted amino)-alkanoates suitable for the presentinvention can be represented by the following formula (V)

-   wherein n is an integer having a value in the range of about 4 to    about 12;-   R is a member of the group consisting of hydrogen, C₁ to C₇ alkyl,    benzyl and phenyl;-   R₁ and R₂ are members of the group consisting of hydrogen and C₁ to    C₇ alkyl; and R₃ and R₄ are members of the group consisting of    hydrogen, methyl and ethyl.

Preferred alkyl (N,N-disubstituted amino)-alkanoates are C₄ to C₁₂ alkyl(N,N-disubstituted amino)-acetates and C₄ to C₁₂ alkyl(N,N-disubstituted amino)-propionates. Exemplary specificalkyl-2-(N,N-disubstituted amino)-alkanoates include dodecyl 2-(N,Ndimethylamino)-propionate (DDAIP); and dodecyl2-(N,N-dimethylamino)-acetate (DDAA).

Alkyl-2-(N,N-disubstituted amino)-alkanoates are known. For example,dodecyl 2-(N,N-dimethylamino)-propionate (DDAIP) is available fromSteroids, Ltd. (Chicago, Ill.). In addition, alkyl-2-(N,N-disubstitutedamino)-alkanoates can be synthesized from more readily availablecompounds as described in U.S. Pat. No. 4,980,378 to Wong et al., whichsyntheses procedures are incorporated herein by reference.

Suitable (N,N-disubstituted amino)-alkanol alkanoates can be representedby the formula (VI):

-   wherein m is an integer having a value in the range of about 5 to    about 22, preferably, from about 5 to about 18; y is an integer    having a value in the range of 0 to about 5; and R₁, R₂, R₃, R₄, R₅,    R₆, and R₇ are members of the group consisting of hydrogen, C₁ to C₈    alkyl, and C₆ to C₈ aryl; and R₈ represents hydrogen, hydroxyl, C₁    to C₈ alkyl, or C₆ to C8 aryl.

Preferred (N,N-disubstituted amino)alkanol alkanoates include C₅ to C₁₈carboxylic acid esters, such as the compounds of the following formula(VI-1):

where m′ is an integer of from about 5 to about 21, preferably, fromabout 5 to about 16; and p is an integer of from 0 to about 3,preferably, 0 or 1, especially 0.

Exemplary specific alkyl alkanoate compounds of formula (V) include1-(N,N-dimethylamino)-2-propanol dodecanoate (DAIPD),1-(N,N-dimethylamino)-2-propanol myristate (DAIPM), and1-(N,N-dimethylamino)-2-propanol oleate (DAIPO).

Among the suitable penetration enhancers for the present invention DDAIPand DAIPD may be specifically mentioned.

Another class of penetration enhancers of type (iv) include N-alkyllactams, such as those disclosed in, for example, U.S. Pat. Nos.4,316,893 and 4,424,210, the disclosures of which are incorporatedherein, in their entirety, by reference thereto; andN-alkylazacycloheptanes, such as those disclosed in, for example, U.S.Pat. No. 5,204,339, the disclosure of which is incorporated herein, inits entirety, by reference thereto.

The N-alkyl lactams include, for example, compounds of the followingformula (VII):

-   where R′ is H or a C₁ to C₄ alkyl group, R is C₁ to C₂ alkyl, phenyl    or substituted phenyl, or the group    m is an integer of 3 to 7, n is 0 or an integer of 1 to 17, except    that when m is 3, n is from 7 to 17, and R is preferably methyl. In    one embodiment, n is an integer such that the total number of carbon    atoms represented by (CH₂)_(n) and R is from about 6 to 12.

A preferred class of lactams are represented by the following formula(VII-1)

where n=0 or an integer from 1 to 10, and n″=0, 1 or 2.

Typical examples of compounds of formula (VII) include:

-   1-n-hexylazacyclopentan-2-one-   1-n-heptaylazacyclopentan-2-one-   1-n-octylazacyclopentan-2-one-   1-n-nonylazacyclopentan-2-one-   1-decylazacyclopentan-2-one-   1-n-dodecylazacyclopentan-2-one-   1-methylazacycloheptan-2-one-   1-n-propylazacycloheptan-2-one-   1-n-butylazacycloheptan-2-one-   1-n-octylazacycloheptan-2-one-   1-phenylazacyclopentan-2-one-   1-(2-chlorophenyl)azacyclopentan-2-one-   1,3-bis-(1-azacyclopentan-2-onyl)propane.

Of these, 1-n-dodecyl-azacycloheptan-2-one, is commercially availableunder the tradename, AZONE.

The N-alkylazacycloheptanes may be represented by the following formula(VIII):

where X represents O or S, preferably O, R′ represents H or C₁ to C₄alkyl; r is an integer of from 2 to 6, and s is 0 or an integer of 1 to17.

Representative compounds of formula (VIII) include:

-   1-n-undecylformylazacycloheptane-   1-n-decylformylazacycloheptane-   1-n-octylformylazacycloheptane-   1-n-nonylformylazacycloheptane-   1-n-dodecylformylazacycloheptane-   1-n-tetradecylformylazacycloheptane-   1-n-hexadecylformylazacycloheptane-   1-n-pentadecylformylazacycloheptane-   1-n-heptadecylformylazacycloheptane-   1-(16-methylhexadecyl)formylazacycloheptane.

Other skin penetration enhancing compounds useful in the presentinvention include alkyl esters.

In one embodiment, the skin penetration enhancing compounds may bepresent from 0 to 25 wt. %, for example, from about 5 to about 20 wt. %,such as from about 7 to about 15 wt. %, or from about 1 to about 25 wt.%, such as from about 2 to about 20 wt. %, or from about 3 to about 15wt. % percent by weight of the composition.

e. Emulsifying Agents

An optional emulsifying agent, when present in an emulsifying effectiveamount, may be used to assist the hydrophobic and hydrophilic componentsin dispersing and forming an essentially uniform micellar compositionwith an appropriate cream consistency. A wide variety of emulsifyingagents may be used. Any emulsifying agent will be suitable so long as iteffectively forms the desired emulsion and does not react with, orprevent delivery of, the active agents. Emulsifying agents may be ionicor neutral.

Examples of suitable emulsifying agents include, disodiumcocoamphodiacetate, oxyethylenated glyceryl cocoate (7 EO) such as theproduct sold by COGNIS under the name Cetiol HE, PEG-20 hexadecenylsuccinate, PEG-15 stearyl ether; the ricinoleic monoethanolamidemonosulfosuccinate salts such as the product sold by Goldschmidt underthe name REWODERM S1333, oxyethylenated hydrogenated ricinoleictriglyceride containing 60 ethylene oxide units such as the product soldby Nikko under the name NIKKOL HCO-60 or such as the product sold byBASF under the name CREMOPHOR RH60 or CREMOPHOR RH 40 (polyoxyl 40hydrogentate castor oil), polymers such as Poloxamers, which are blockcopolymers of ethylene oxide and propylene oxide, such as for examplethe product sold under the name Lutrol F68 by BASF and Poloxamer 407sold under the name SYNPERONIC PE/F 127 by UNIQEMA The nonsolid fattysubstances at room temperature (that is to say at a temperature rangingfrom about 20 to 35° C. such as sesame oil, sweet almond oil, apricotstone oil, sunflower oil, octoxyglyceryl palmitate (or 2-ethylhexylglyceryl ether palmitate) such as the product marketed under the nameMexanyl GP by the company Chimex, octoxyglyceryl behenate (or2-ethylhexyl glyceryl ether behenate), dioctyl adipate, tartrate ofbranched C₁₂-C₁₃ dialcohols such as the product sold under the nameCosmacol ETI by Enichem.

Nonionic emulsifying agents include those that can be broadly defined ascondensation products of long chain alcohols, e.g. C₈-₃₀ alcohols, withsugar or starch polymers, i.e., glycosides. These compounds can berepresented by the formula (S)_(n)—O—R wherein S is a sugar moiety suchas glucose, fructose, mannose, and galactose; n is an integer of fromabout 1 to about 1000, and R is a C₈₋₃₀ alkyl group. Examples of longchain alcohols from which the alkyl group can be derived include decylalcohol, cetyl alcohol, stearyl alcohol, lauryl alcohol, myristylalcohol, oleyl alcohol, and the like. Preferred examples of theseemulsifying agents include those wherein S is a glucose moiety, R is aC₈₋₂₀ alkyl group, and n is an integer of from about 1 to about 9.Commercially available examples of this type of emulsifying agentsinclude decyl polyglucoside (available as APG 325 CS from Henkel) andlauryl polyglucoside (available as APG 600 CS and 625 CS from Henkel).

Other useful nonionic emulsifying agents include the condensationproducts of alkylene oxides with fatty acids (i.e. alkylene oxide estersof fatty acids). These materials have the general formula RCO(X)_(n)OHwherein R is a C₁₀₋₃₀ alkyl group, X is —OCH₂CH₂— (i.e. derived fromethylene glycol or oxide) or —OCH₂CHCH₃— (i.e. derived from propyleneglycol or oxide), and n is an integer from about 6 to about 200. Othernonionic surfactants are the condensation products of alkylene oxideswith 2 moles of fatty acids (i.e. alkylene oxide diesters of fattyacids). These materials have the general formula RCO(X)_(n)OOCR whereinR is a C₁₀₋₃₀ alkyl group, X is —OCH₂CH₂— (i.e. derived from ethyleneglycol or oxide) or —OCH₂CHCH₃— (i.e. derived from propylene glycol oroxide), and n is an integer from about 6 to about 100. Other nonionicemulsifying agents are the condensation products of alkylene oxides withfatty alcohols (i.e. alkylene oxide ethers of fatty alcohols). Thesematerials have the general formula R(X)_(n)OR′ wherein R is a C₁₀₋₃₀alkyl group, X is —OCH₂CH₂— (i.e. derived from ethylene glycol or oxide)or —OCH₂CHCH₃— (i.e. derived from propylene glycol or oxide), and n isan integer from about 6 to about 100 and R′ is H or a C₁₀₋₃₀ alkylgroup. Still other nonionic emulsifying agents are the condensationproducts of alkylene oxides with both fatty acids and fatty alcohols[i.e., wherein the polyalkylene oxide portion is esterified on one endwith a fatty acid and etherified (i.e. connected via an ether linkage)on the other end with a fatty alcohol]. These materials have the generalformula RCO(X)_(n)OR′ wherein R and R″ are C₁₀₋₃₀ alkyl groups, X is—OCH₂CH₂ (i.e. derived from ethylene glycol or oxide) or —OCH₂CHCH₃—(derived from propylene glycol or oxide), and n is an integer from about6 to about 100. Non-limiting examples of these alkylene oxide derivednonionic emulsifying agents include ceteth-6, ceteth-10, ceteth-12,ceteareth-6, ceteareth-10, ceteareth-12, steareth-6, steareth-10,steareth-12, PEG-6 stearate, PEG-10 stearate, PEG-100 stearate, PEG-12stearate, PEG-20 glyceryl stearate, PEG-80 glyceryl tallowate, PEG-10glyceryl stearate, PEG-30 glyceryl cocoate, PEG-80 glyceryl cocoate,PEG-200 glyceryl tallowate, PEG-8 dilaurate, PEG-10

Other nonionic emulsifying agents include sugar esters and polyesters,alkoxylated sugar esters and polyesters, C₁-C₃₀ fatty acid esters ofC₁-C₃₀ fatty alcohols, alkoxylated derivatives of C₁-C₃₀ fatty acidesters of C₁-C₃₀ fatty alcohols, alkoxylated ethers of C₁-C₃₀ fattyalcohols, polyglyceryl esters of C₁-C₃₀ fatty acids, C₁-C₃₀ esters ofpolyols, C₁-C₃₀ethers of polyols, alkyl phosphates, polyoxyalkylenefatty ether phosphates, fatty acid amides, acyl lactylates, and mixturesthereof. Non-limiting examples of these emulsifying agents include:polyethylene glycol 20 sorbitan monolaurate (Polysorbate 20),polyethylene glycol 5 soya sterol, Steareth-20, Ceteareth-20, PPG-2methyl glucose ether distearate, Ceteth-10, Polysorbate 80, cetylphosphate, potassium cetyl phosphate, diethanolamine cetyl phosphate,Polysorbate 60, glyceryl stearate, polyoxyethylene 20 sorbitan trioleate(Polysorbate 85), sorbitan monolaurate, polyoxyethylene 4 lauryl ethersodium stearate, polyglyceryl-4 isostearate, hexyl laurate, PPG-2 methylglucose ether distearate, PEG-100 stearate, and mixtures thereof.Further examples of suitable emulsifiers include mixtures of stearyloctanoate and isopropyl myristate, or mixtures of cetyl octanoate andstearyl octanoate, such those available as Dub Liquide 85 IP, or DubLiquide from Sterineries de Dubois.

Other emulsifying agents useful herein are fatty acid ester blends basedon a mixture of sorbitan or sorbitol fatty acid ester and sucrose fattyacid ester, the fatty acid in each instance being preferably C₈-C₂₄,such as C₁-C₂₀. In one embodiment the fatty acid ester emulsifier is ablend of sorbitan or sorbitol C₁₆-C₂₀ fatty acid ester with sucroseC₁₀-C₁₆ fatty acid ester, especially sorbitan stearate and sucrosecocoate. This is commercially available from ICI under the trade nameArlatone 2121.

Emulsifying agents can also include any of a wide variety of cationic,anionic, zwitterionic, and amphoteric surfactants such as are known inthe art. See, e.g., McCutcheon's, Detergents and Emulsifiers, NorthAmerican Edition (1986), published by Allured Publishing Corporation;U.S. Pat. No. 5,011,681 to Ciotti et al., issued Apr. 30, 1991; U.S.Pat. No. 4,421,769 to Dixon et al., issued Dec. 20, 1983; and U.S. Pat.No. 3,755,560 to Dickert et al., issued Aug. 28, 1973; these fourreferences are incorporated herein by reference in their entirety.

Exemplary cationic emulsifying agents include those disclosed in U.S.Pat. No. 5,151,209, to McCall et al., issued Sep. 29, 1992; U.S. Pat.No. 5,151,210, to Steuri et al., issued Sep. 29, 1992; U.S. Pat. No.5,120,532, to Wells et al., issued Jun. 9, 1992; U.S. Pat. No.4,387,090, to Bolich, issued Jun. 7, 1983; U.S. Pat. 3,155,591, Hilfer,issued Nov. 3, 1964; U.S. Pat. No. 3,929,678, to Laughlin et al., issuedDec. 30, 1975; U.S. Pat. No. 3,959,461, to Bailey et al., issued May 25,1976; McCutcheon's, Detergents & Emulsifiers, (North American edition1979) M.C. Publishing Co.; and Schwartz, et al., Surface Active Agents,Their Chemistry and Technology, New York: Interscience Publishers, 1949;all of these documents being incorporated herein by reference in theirentirety. The cationic surfactants useful herein include cationicammonium salts such as quaternary ammonium salts, and amino-amides.

Anionic emulsifying agents are described, e.g., in U.S. Pat. No.3,929,678, to Laughlin el al., issued Dec. 30, 1975, which isincorporated herein by reference. Non-limiting examples of anionicemulsifying agents include the alkoyl isethionates (e.g., C₁₂-C₃₀),alkyl and alkyl ether sulfates and salts thereof, alkyl and alkyl etherphosphates and salts thereof, alkyl methyl taurates (e.g., C₁₂-C₃₀), andsoaps (e.g., alkali metal salts, e.g., sodium or potassium salts) offatty acids.

Examples of amphoteric and zwitterionic emulsifying agents are thosewhich are broadly described as derivatives of aliphatic secondary andtertiary amines in which the aliphatic radical can be straight orbranched chain and wherein one of the aliphatic substituents containsfrom about 8 to about 22 carbon atoms (preferably C₈-C₁₈) and onecontains an anionic water solubilizing group, e.g., carboxy, sulfonate,sulfate, phosphate, or phosphonate. Examples are alkyl imino acetates,and iminodialkanoates and aminoalkanoates, imidazolinium and ammoniumderivatives. Other suitable amphoteric and zwitterionic emulsifyingagents are those selected from the group consisting of betaines,sultaines, hydroxysultaines, alkyl sarcosinates (e.g., C₁₂-C₃₀), andalkanoyl sarcosinates.

These silicone emulsifying agents are typically organically modifiedorganopolysiloxanes, also known to those skilled in the art as siliconesurfactants. Useful silicone emulsifying agents include dimethiconecopolyols. These materials are polydimethyl siloxanes which have beenmodified to include polyether side chains such as polyethylene oxidechains, polypropylene oxide chains, mixtures of these chains, andpolyether chains containing moieties derived from both ethylene oxideand propylene oxide. Other examples include alkyl-modified dimethiconecopolyols, i.e., compounds which contain C₂-C₃₀ pendant side chains.Still other useful dimethicone copolyols include materials havingvarious cationic, anionic, amphoteric, and zwitterionic pendantmoieties.

Non-limiting examples of dimethicone copolyols and other siliconeemulsifying agents useful herein include polydimethylsiloxane polyethercopolymers with pendant polyethylene oxide side chains,polydimethylsiloxane polyether copolymers with pendant polypropyleneoxide side chains, polydimethylsiloxane polyether copolymers withpendant mixed polyethylene oxide and polypropylene oxide side chains,polydimethylsiloxane polyether copolymers with pendant mixedpoly(ethylene)(propylene)oxide side chains, polydimethylsiloxanepolyether copolymers with pendant organobetaine side chains,polydimethylsiloxane polyether copolymers with pendant carboxylate sidechains, polydimethylsiloxane polyether copolymers with pendantquaternary ammonium side chains; and also further modifications of thepreceding copolymers containing pendant C2-C30 straight, branched, orcyclic alkyl moieties. Examples of commercially available dimethiconecopolyols useful herein sold by Dow Corning Corporation are Dow Coming®190, 193, Q2-5220, 2501 Wax, 2-5324 fluid, and 3225C (this latermaterial being sold as a mixture with cyclomethicone). Cetyl dimethiconecopolyol is commercially available as a mixture with polyglyceryl-4isostearate (and) hexyl laurate and is sold under the trade name ABIL(®WE-09 (available from Goldschmidt). Cetyl dimethicone copolyol is alsocommercially available as a mixture with hexyl laurate (and)polyglyceryl-3 oleate (and) cetyl dimethicone and is sold under thetrade name ABIL® WS-08 (also available from Goldschmidt). Othernon-limiting examples of dimethicone copolyols also include lauryldimethicone copolyol, dimethicone copolyol acetate, dimethicone copolyoladipate, dimethicone copolyolamine, dimethicone copolyol behenate,dimethicone copolyol butyl ether, dimethicone copolyol hydroxy stearate,dimethicone copolyol isostearate, dimethicone copolyol laurate,dimethicone copolyol methyl ether, dimethicone copolyol Phosphate, anddimethicone copolyol stearate. See International Cosmetic IngredientDictionary, Fifth Edition, 1993, which is incorporated by referenceherein in its entirety.

In one embodiment, the emulsifying agent is PEG-40 hydrogenated castoroil, such as the commercially available Cremophor® RH 40. In oneembodiment, the emulsifying agent is present from between about 0.1 toabout 25 wt. %, for example, about 2.5 to about 20 wt. %, such as about5 to about 15 wt. %, relative to the total weight of the composition.

3. Other Components

The topical compositions of the present invention may include a widevariety of optional components, provided that such optional componentsare physically and chemically compatible with the essential componentsdescribed herein, and do not unduly impair stability, efficacy or otheruse benefits associated with the compositions of the present invention.Optional components may be dispersed, dissolved or the like in the creambase of the present compositions.

As with the above described components, all of the ingredients used inthe components according to the embodiments of the present inventionintended for application to humans or other animals, e.g., mammals, suchas dogs, cats, horses, cows and other domesticated animals, should benon-toxic (or used in non-toxic quantities) and pharmacologically andpharmaceutically safe for such intended use.

Optional components include, for example, aesthetic agents, absorbents(including oil absorbents such as clays an polymeric absorbents),abrasives, anti-caking agents, antifoaming agents, antimicrobial agents(e.g., a compound capable of destroying microbes, preventing thedevelopment of microbes or preventing the pathogenic action of microbesand useful, for example, in controlling acne and/or preserving thetopical composition), binders, biological additives, buffering agents,bulking agents, chemical additives, cosmetic biocides, denaturants,cosmetic astringents, drug astringents, external analgesics, filmformers, humectants, emollients, opacifying agents, fragrances,perfumes, pigments, colorings, essential oils, emollients, skin soothingagents, skin healing agents, pH adjusters, plasticizers, preservatives,preservative enhancers, propellants, reducing agents, skin-conditioningagents, skin protectants, solvents, suspending agents, thickeningagents, solubilizing agents, polymers for aiding the film-formingproperties and substantively of the composition (such as a copolymer ofeicosene and vinyl pyrrolidone, an example of which is available fromGAF Chemical Corporation as Ganex) V-220), waxes, sunscreens, sunblocks,ultraviolet light absorbers or scattering agents, antioxidants and/orradical scavengers, chelating agents, sequestrants, anti-acne agents,anti-inflammatory agents, anti-androgens, depilation agents,desquamation agents/exfoliants, organic hydroxy acids, vitamins andderivatives thereof (including water dispersible or soluble vitaminssuch as Vitamin C and ascorbyl phosphates), compounds which stimulatecollagen production, and natural extracts. Such other materials areknown in the art. Nonexclusive examples of such materials are describedin Harry's Cosmeticology, 7th Ed., Harry & Wilkinson (Hill Publishers,London 1982); in Pharmaceutical Dosage Forms—Disperse Systems;Lieberman, Rieger & Banker, Vols. 1 (1988) & 2 (1989); Marcel Decker,Inc.; in The Chemistry and Manufacture of Cosmetics, 2nd. Ed., deNavarre(Van Nostrand 1962-1965); and in The Handbook of Cosmetic Science andTechnology, 1st Ed. Knowlton & Pearce (Elsevier 1993), can also be usedin the present invention.

In one embodiment, the carrier includes an additional thickening agent.For example, mention may be made of other cellulosic ethers, polymericthickening agents, e.g., acrylic acid polymers, Carbopol® thickeners,etc., xanthan gum, guar gum, and the like, as well as inorganicthickeners/gelling agents. The amount of the thickening agent can beselected to provide the desired product consistency or viscosity toallow for easy application but which will not be too watery or loose sothat it will stay where applied. Amounts of thickening agent, up toabout 5 wt. % of the total composition, such as between 0.5 and 5 wt. %,such as 2 to 5 wt. %, may be used in the compositions of the presentinvention.

4. Application

In one embodiment, the amount of formulation to be applied is in therange of from about 0.1 to about 1 milliliter (ml), such as from about0.1 to 0.5 ml, or from about 0.2 to 0.3 ml. For these embodiments, theapplication rates the active agents will be contained in the formulationin the amounts as described above, namely, from about 0.001 to 5.0 wt.%, such as 0.05 to 1.5 wt. %, and in another embodiment from about 0.05to 1.0 wt %.

For a typical, representative formulation according to the inventioncontaining 1 wt. % of PGE-1 and 10 wt. % of 2-n-nonyl-1,3-dioxolane,suitable dosage amounts, as a function of the intended use and area ofapplication, may be from about 0.1 to about 0.5 ml, such as from about0.2 to 0.3 ml, such as, for example, 0.25 ml.

In one embodiment of the present invention, a method is provided foradministering an active agent to the skin of person in need thereof, byapplying the compositions of the present invention to the skin of theperson in need of treatment.

The compositions of the present invention may be applied to the skin byany suitable means. For example, the composition may be applied directlyto the desired area as a cream, or the cream may be applied by means ofan aerosol, spray, pump-pack, brush, swab, or other applicator. In oneembodiment, the applicator provides either a fixed or variable metereddose application such as a metered dose aerosol, a stored-energy metereddose pump or a manual metered dose pump.

The compositions of the present invention may be propelled by eitherpump pack or by the use of propellants such as hydrocarbons,hydrofluorocarbons, nitrogen, nitrous oxide, carbon dioxide or ethers,preferably dimethyl ether. The non-occlusive, drug delivery system ispreferably in a single phase system as this allows less complicatedmanufacture and ease of dose uniformity. It may also be necessary toapply a number of dosages on untreated skin to obtain the desiredresult.

In addition to the above different forms of the composition, thecompositions may also be provided for administration by any of the knowndelivery forms, including, for example, unit dosage and multi-dosage(i.e., multiple unit dosages in a single package or container) forms andbulk forms. As examples of unit dosage forms, mention may be made, forexample, of syringes, gelcaps, blister packs, and the like. Bulk formsmay be stored in, for example, tubes, bottles, jars, pumps, aerosolcontainers, and the like, formed of glass, coated metal containers orplastic materials. Again, the formulation and packaging ofpharmaceutical products is well within the skill in the art.

The compositions of this invention tend to remain stable against phaseseparation and product degradation over a wide range of storageconditions. For example, the cream compositions as described above mayremain stable over a temperature range of at least from about −20 to 40°C., over periods of several months to years, depending on the storagetemperature. It will he understood by one of ordinary skill in the artthat stability of a composition to phase separation will be influencedby the conditions under which the composition was formed and stored.

According to an embodiment of the invention, it is possible to use lessof the active agent than in current commercial or clinically testedproducts, thereby lessening the likelihood of adverse reactions,irritation or other side effects.

The compositions of the present invention may also be used to treatdiseases in non-human animals. Such veterinary formulations of thepresent invention can be used with any of the known classes and types ofveterinary drug products. For instance, mention may be made of thefollowing: analeptics, such as, for example, diazepam,thiamylal/thipental, midazolam, phentobarbital, phenobarbital;anesthetics, such as, for example, alpha chloralose/chloral hydrate,benzocaine, droperidol/fentanyl, ether, haloethane, isoflurane,ketamine, lidocaine, methohexital, tricaine; antifungals, such as, forexample, griseofulvin, ketoconazole; antihistamines, such as, forexample, chlorpheniramine, cimetidine, diphenhydramine; antimicrobials,such as, for example, amoxicillin, ampicillin, amoxicillin, clavulinate,cephalosporins, ciproflxacin, clindamycin, doxycycline, enrofloxacin,erthhromycin, gentamicin, lincomycin, minocycline, neomycin,oxytetracycline, penicillin, rifampin, tetracycline, ticarcillin,trimethoprim/sulfonamide; autonomic drugs, such as, for example,atropine, bethanechol, glycopyrrolate; cardiac drugs, such as, forexample, captopril, digoxin, epinephrine, furosemide (lasix),procainamide, propanolol, methionine D-L, potassium, selenium/Vitamin E,taurine, Vitamin A & D, Vitamin B complex, Vitamin C, Vitamin D, VitaminK; gastrointestinal agents, such as, for example, chlorpromazine,cimetidine, metoclopramide, ranitidine; hormones, such as, for example,dexamethasone, dinoprost, estradiol cypionate, fludrocortisone,levothyroxine, methylprednisolone, misoprostol, oxytocin,prednisone/Prednisolone, triamcinolone; muscle relaxants, such as, forexample, gallamine, guaifenesin, methocarbinol, metocurine iodide,succinylcholine, tubocurarine; narcotics/analgesics, such as, forexample, hydrocodone, naloxone; non-steroidalantiinflammatory/analgesics, such as, for example, acetaminophen,carprofen, flunixin, ibuprofen, ketoprofen, phenylbutazone; respiratorydrugs, such as, for example, aminophyline, dextromethorphan,hydrocodone; sedatives, such as, for example, acepromazine, azaperone,diazepam, medetomidine, midazolam, propofol, xylazine; and miscellaneousother drugs, such as, for example, heparin (anticoagulant), insulin(diabetes), methimazole (hyperthyroidism), and the like.

The compositions of the present invention may also include anthelminticcompositions suitable for controlling pathogenic endoparasitesencountered in horses in animal keeping and livestock breeding; and inhousehold pets, particularly cats and dogs. They have a favorabletoxicity to warm-blooded species. They are effective against all orindividual developmental stages of the pests and against resistant andnormally sensitive species. The pathogenic endoparasites includeCestodes, Trematodes, Nematodes and Acanthocephala, in particular:

From the order of the Pseudophyllidea, for example: Diphyllobothriumspp., Spirometra spp., Schistocephalus spp.

From the order of the Cyclophyllidea, for example: Mesocestoides spp.,Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Taenia spp.,Echinococcus spp., Hydatigera spp., Diorchis spp., Dipylidium spp.,Joyeuxiella spp., Spyrometra spp.

From the subclass of the Digenea, for example: Schistosoma spp.,Fasciola spp., Dicrocoelium spp., Opisthorchis spp.

From the order of the Enoplida, for example: Trichuris spp., Capillariaspp., Trichinella spp.

From the order of the Rhabditia, for example: Micronema spp.,Strongyloides spp.

From the order of the Strongylida, for example: Stronylus spp.,Triodontophorus spp., Oesophagodontus spp., Trichonema spp.,Gyalocephalus spp., Poteriostomum spp., Cyclicocyclus spp., Stephanurusspp., Ancyclostoma spp., Uncinaria spp., Cyathostomum spp.,Metastrongylus spp., Dictyocaulus spp., Muellerius spp., Protostrongylusspp., Elaphostrongylus spp., Parelaphostrongylus spp., Crenosoma spp.,Paracrenosoma spp., Filaroides spp., Parafilaroides spp., Marshallagiaspp., Hyostrongylus spp., Ollulanus spp., Craterostomum spp.,Cyclicodontophorus spp., Hyalocephalus spp., Cylindropharynx spp.,Caballonema spp., Elaeophorus spp., Dirofilaria spp., Onchocerca spp.,Setaria spp.

From the order of the Oxyurida, for example: Oxyuris spp., Enterobiusspp.

From the order of the Ascaridia, for example: Ascaris spp., Toxascarisspp., Toxocara spp., Parascaris spp., Probstmangria spp.

From the order of the Spirurida, for example: Thelazia spp., Habronemaspp., Draschia spp., Dracunculus spp.

The product can be administered both prophylactically andtherapeutically.

Anthelmintics include those which comprise praziquantel or epsiprantel,as hexahydropyrazino derivatives. In addition to thehexahydropyrazinones, the anthelmintic formulations according to theinvention can also comprise other active agents. These arephenylguanidines, benzimidazoles or tetrahydropyrimidines. See U.S. Pat.No. 6,025,357 for representative examples, the mention of which isincorporated herein by reference thereto.

The phenylguanidines include, for example, febantel and netobimine.

The benzimidazoles are, for example, febendazole, albendazole,oxibendazole, oxfendazole, mebendazole, flubendazole, parbendazole andluxabendazole.

The tetrahydropyrimidines include, for example, pyrantel, morantel andoxantel.

Other anthelmintic drugs which may be advantageously used in thecompositions of this invention include ivermectin, metronidazole,milbemycin oxime, and selamectin.

EXAMPLES

General Considerations

Preparation of Test Creaytis

Sample emulsion batches of 100 g were prepared in the following manner.The desired quantities of ethanol, Cremophor RH40, and SEPA 0009®(2-n-nonyl-1,3-dioxolane; from MacroChem Corporation, Lexington, Mass.)were combined with slow agitation using a stirrer bar in a jar, andmixed until a clear solution was obtained. To a separate 250 mL beakerwas added the desired amount of water. With propeller mixing, thedesired amount of Sepigel, Simulgel, or Aristoflex was added to thebeaker. Then, the previously prepared mixture of ethanol, Cremophor RH40 and SEPA 0009® was transferred by pipette to the above describedcream base. Finally, Germaben II-E was added to the beaker, and stirringcontinued for 25 to 30 minutes to obtain the desired cream formulationThe composition of the various cream bases are set fourth in Table 1.

PGE₁ (Lot 438020A) was obtained from Spolana (Prague). SEPA 0009® fromMacroChem Corporation (Lexington, Mass.). Ethanol was obtained fromAaper Alcohol (Shelbyville, Ky.). Propylene glycol and isopropanol wereobtained from Spectrum (New Brunswick, N.J.). Sepigel and Simulgel wereobtained from Seppic, Inc. (Fairfield, N.J.). Cremophor RH 40 wassupplied by BASF (Wyandotte, N.J.) and Germaben II-E by ISP Sutton(Chatham, N.J.). Water was deionized using a Milli-Q system fromMillipore Corp. (Bedford, Mass.).

Physical Results: Test creams were determined to have an acceptableinitial physical consistency if they were visually observed to form anemulsion upon mixing that did not readily separate under ambientconditions.

Stability to centrifugation: Test creams were judged to be stable tocentrifugation if they were unchanged visibly (naked eye and microscope)after centrifugation at 1300G for up to two hours, if no inhomogeneitieswere observed (in particular the crystallization of drug), and if assaysshowed potency within 10% of calculated active agent and SEPAL.Representative products (formulation numbers 11, 13 and 16) showingcontinued stability (1 week minimum) were submitted for transdermaltesting, as further described below. TABLE 1 FORMULATION 1 2 3 4 5 6 7 89 10 11 12 SEPA 0009 5 5 5 5 5 5 5 5 10 5 10 10 PGE1 1 2 1 2 1 2 1 1 1 21 Testosterone 1 Ibuprofen Hydroquinone Methylphenidate HCl Sepigel 3054 4 4 4 4 4 4 4 4 4 Simulgel 600 4 4 Aristoflex Cetearyl Octanoate 5 5 5Cremophor RH 40 15 5 5 5 5 5 5 5 5 5 5 Tween 80 Tween 60 Volpo S-20Cetomacrogol 1000 Glucamate SSE-20 Phospholipon 90H Sesame Oil DubLiquide White Mineral Oil Ethanol 25 40 40 40 40 40 40 50 40 50 40 40Miglyol 812N (Caprylic/ 5 capric triglyceride) Propylene Glycol 5Germaben II-E 1 1 1 1 1 1 1 1 1 1 1 1 H2O 34 43.5 42.5 39 38 44 43 34 3939 38 39 1% Citric Acid 0.5 0.5 Ascorbic acid NaOH (2.5%) Total 100 100100 100 100 100 100 100 100 100 100 100 pH 6.9 5.1 4.9 5.3 5.1 5.3 5.05.6 5.4 5.2 5.2 5.6 Physical Results P P P P P P P P P P P P Stable tocentrifugation? nt Y Y Y Y Y Y Y Y Y Y Y FORMULATION 13 14 15 16 17 1819 20 21 22 23 24 SEPA 0009 10 10 7.5 7.5 5 7.5 7.5 7.5 7.5 7.5 5 7.5PGE1 1 2 2 2 1 1 1 1.5 1.5 1.5 Testosterone 1 1 Ibuprofen HydroquinoneMethylphenidate HCl Sepigel 305 4 4 4 4 Simulgel 600 4 4 4 4 4 4 5 5Aristoflex — Cetearyl Octanoate Cremophor RH 40 2.5 2.5 2.5 2.5 2.5 2.52.5 2.5 2.5 2.5 2.5 2.5 Tween 80 Tween 60 Volpo S-20 Cetomacrogol 1000Glucamate SSE-20 Phospholipon 90H Sesame Oil Dub Liquide White MineralOil Ethanol 40 40 40 40 40 40 40 40 40 40 40 40 Miglyol 812N (Caprylic/capric triglyceride) Propylene Glycol 5 5 Germaben II-E 1 1 1 1 1 1 1 11 1 1 1 H2O 41.5 40.5 43 43 46.5 44 44 44 44 44 41 38 1% Citric AcidAscorbic acid NaOH (2.5%) Total 100 100 100 100 100 100 100 100 100 100100 100 pH 5.6 5.3 4.9 5.1 5.3 5.3 5.1 4.9 5.2 5.2 6.8 6.6 PhysicalResults P P P P P P P P P P P P Stable to Y Y Y Y Y Y Y Y Y Y Y Ycentrifugation? FORMULATION 25 26 27 28 29 30 31 32 33 34 35 36 SEPA0009 7.5 10 5 5 5 5 5 5 5 10 5 5 PGE1 Testosterone 1 1 1 1 1 1 1 1 1 1 11 Ibuprofen Hydroquinone Methylphenidate HCl Sepigel 305 Simulgel 600 55 5 5 5 5 5 5 5 5 Aristoflex 0.5 1 Cetearyl Octanoate Cremophor RH 40 52.5 2.5 2.5 2.5 2.5 Tween 80 2.5 Tween 60 2.5 Volpo S-20 2.5Cetomacrogol 1000 2.5 Glucamate SSE-20 2.5 Phospholipon 90H 2.5 SesameOil Dub Liquide White Mineral Oil Ethanol 40 40 40 40 40 40 40 40 40 4040 40 Miglyol 812N (Caprylic/ capric triglyceride) Propylene Glycol 5 55 5 5 5 5 5 5 5 5 5 Germaben II-E 1 1 1 1 1 1 1 1 1 1 1 1 H2O 36 36 4141 41 41 41 41 41 36 45 45 1% Citric Acid Ascorbic acid NaOH (2.5%)Total 100 100 100 100 100 100 100 100 100 100 100 100 pH 6.6 6.5 6.7 4.96.4 6.3 6.4 6.5 6.5 6.7 5.3 6.2 Physical Results P P P P P P P P P P P PStable to centrifugation? Y Y Y N N N N N N Y nt Y FORMULATION 37 38 3940 41 42 43 44 45 46 47 48 SEPA 0009 5 0 0 5 10 10 10 7.5 5 5 5 5 PGE1 11 1 Testosterone 1 Ibuprofen 5 5 5 5 Hydroquinone 3 3 3 Methylphenidate2 HCI Sepigel 305 Simulgel 600 3 3.5 3.5 4 4.5 5 4 5 5 5 2.5 Aristoflex1 Cetearyl Octanoate Cremophor RH 40 2.5 2.5 2.5 1 2.5 2.5 1 2.5 Tween80 Tween 60 Volpo S-20 Cetomacrogol 1000 Glucamate SSE-20 Phospholipon90H Sesame Oil Dub Liquide White Mineral Oil Ethanol 40 41 45 45 40 4030 40 40 Miglyol 812N (Caprylic/capric triglyceride) Propylene Glycol 55 5 5 Germaben II-E 1 1 1 1 1 H2O 47 89 88 83 41.5 37 36.5 54.5 41.546.5 38 39 1% Citric Acid Ascorbic acid 0.5 0.5 0.5 NaOH (2.5%) 5 5 5 YY Y Y Total 100 100 100 100 100 100 100 100 100 100 100 100 pH 6.2 — 5.25.2 5.5 4.8 4.8 nt 7.02 6.62 6.61 6.62 Physical Results P F F F P P P FF F F F Stable to N nt nt nt Y Y Y nt nt nt nt nt centrifugation?FORMULATION 49 50 51 52 53 54 55 56 57 58 59 60 SEPA 0009 5 5 5 5 5 5 55 5 5 5 5 PGE1 Testosterone Ibuprofen 5 5 5 5 5 5 5 5 5 5 5 5Hydroquinone Methylphenidate HCl Sepigel 305 Simulgel 600 5 5 5 5 5 5 55 2.5 5 5 5 Aristoflex Cetearyl Octanoate Cremophor RH 40 2.5 2.5 5 72.5 2.5 5 7 2.5 1 0 2.5 Tween 80 Tween 60 Volpo S-20 Cetomacrogol 1000Glucamate SSE-20 Phospholipon 90H Sesame Oil Dub Liquide White MineralOil Ethanol 30 20 40 40 15 15 15 15 15 15 15 10 Miglyol 812N (Caprylic/capric triglyceride) Propylene Glycol 5 5 5 Germaben II-E 1 1 1 1 1 1 11 1 1 1 1 H2O 51.5 61.5 34 32 66.5 61.5 64 62 69 68 69 71.5 1% CitricAcid Ascorbic acid NaOH (2.5%) Y Y Y Y Y Y Y Y Y Y Y Y Total 100 100 100100 100 100 100 100 100 100 100 100 pH 6.62 6.65 6.63 6.54 6.64 6.646.63 6.65 6.63 6.64 6.65 6.63 Physical Results F P F F P P P P P P P PStable to nt Y nt nt Y N Y Y N Y N Y centrifugation? FORMULATION 61 6263 64 65 66 67 68 69 70 SEPA 0009 0 0 0 0 0 0 0 0 0 5 PGE1 TestosteroneIbuprofen 5 5 5 5 5 5 5 5 5 5 Hydroquinone Methylphenidate HCl Sepigel305 Simulgel 600 5 5 5 5 5 5 5 5 5 5 Aristoflex Cetearyl OctanoateCremophor RH 40 2.5 2.5 5 7 1 2.5 2.5 2.5 2.5 7 Tween 80 Tween 60 VolpoS-20 Cetomacrogol 1000 Glucamate SSE-20 Phospholipon 90H Sesame Oil DubLiquide White Mineral Oil 5 5 Ethanol 20 15 15 15 15 17.5 18.5 20 15 20Miglyol 812N (Caprylic/ capric triglyceride) Propylene Glycol GermabenII-E 1 1 1 1 1 1 1 1 1 1 H2O 66.5 71.5 69 67 73 69 68 61.5 66.5 57 1%Citric Acid Ascorbic acid NaOH (2.5%) Y Y Y Y Y Y Y Y Y Y Total 100 100100 100 100 100 100 100 100 100 pH 6.63 6.65 6.64 6.65 6.64 6.66 6.656.63 6.66 6.75 Physical Results P P P P P F P P F P Stable tocentrifugation? Y N N Y N nt Y N nt N FORMULATION 71 72 73 74 SEPA 00090 0 0 0 PGE1 Testosterone Ibuprofen 5 5 5 5 Hydroquinone MethylphenidateHCl Sepigel 305 Simulgel 600 5 5 5 5 Aristoflex Cetearyl OctanoateCremophor RH 40 2.5 2.5 2.5 2.5 Tween 80 Tween 60 Volpo S-20Cetomacrogol 1000 Glucamate SSE-20 Phospholipon 90H Sesame Oil 5 DubLiquide 5 5 5 White Mineral Oil Ethanol 15 20 30 20 Miglyol 812N(Caprylic/ capric triglyceride) Propylene Glycol Germaben II-E 1 1 1 1H2O 66.5 61.5 51.5 61.5 1% Citric Acid Ascorbic acid NaOH (2.5%) Y Y Y YTotal 100 100 100 100 pH 6.64 6.65 6.64 6.64 Physical Results P P P PStable to centrifugation? Y N N YP = Pass; F = Fail; Y = Yes; N= No; nt = not testedTransdermal Test Procedures

Preparation of skin: Human cadaver skin was obtained from AATBaccredited tissue banks. The tissue was recovered within 15 hours ofdeath or within 24 hours if the body was refrigerated. It was retrievedunder aseptic technique, quarantined, and placed in antibiotics(Penicillin 50,000 U/Gentamicin 10 mg). Prior to cryopreservation,dermatomed skin grafts were rinsed, cut and measured. Skin thicknessranged between 250-800 μm. Skin grafts were then placed between gauze,folded and placed into a cryo-foil package with 5 mL of cryo-protectant(15% (w/w) glycerin in Lactated Ringer, USP). Antibiotics were added tothe cryoprotectant. The packages were sealed and the tissue was frozenusing control-rate freezing (1° C./5 minutes) to a temperature of −70°C. or lower. Skin samples were stored in a freezer at −20° C. One dayprior to use, the skin was quickly thawed at 4° C., rinsed with tapwater, washed with phosphate buffered saline solution, and blotted dry.Skin circlets were punched and mounted onto diffusion cells. All donorsfrom whom these allografts were derived had been tested and foundnegative for hepatitis B surface antigen and antibodies humanimmunodeficiency viruses (HIV-1 and HIV-2), hepatitis C virus (HCV),hepatitis B surface antigen (HbsAg), hepatitis B core (HbcAB Igm),HTLV-1, and syphilis by FDA approved tests in CLIA approvedlaboratories.

Skin permeation methodology: Percutaneous absorption was measured usinghorizontal glass diffusion cells consisting of a donor and a receptorcompartment (Cf. FIG. 1). Such cells are referred to as Franz-typediffusion cells, or static cells, and were supplied by Crown GlassCompany (Somerville, N.J., U.S.A). Dermatomed skin samples were punchedout with a metallic punch, and placed between the two halves of adiffusion cell, the stratum corneum facing the donor compartment. Thetest apparatus is shown schematically in FIG. 1. The area available fordiffusion was 0.635 cm² and the receptor compartment volume was 5.5 mL.The receptor chamber was filled, so the liquid interfaced with the skinmembrane, with approximately 5 mL phosphate buffered saline (pH 7.4) andallowed to equilibrate to the correct temperature. Temperature of theskin surface was maintained at 32° C. throughout the experiment byplacing diffusion cells into dry block heater set on 37° C. The receptorcompartment contents were continuously agitated by small PTFE-coatedmagnetic stirring bars at 600 rpm.

Skin samples were allowed to equilibrate with phosphate buffered salinewith 0.2% Volpo 20 for at least one hour before application of testformulations on the morning of the experiment. Formulations were appliedusing a 50 μL dispensing pipette (VWR). The pipette was weighed beforeand after application and the exact amounts applied were recorded.Target application amount was between 5 and 10 mg/cm² of formulation.Following application of the products, the entire receptor phase wasremoved at regular time intervals, 2, 4, 6, 8, and 24 hours, using a 5mL syringe. The receptor compartment was then refilled with freshtemperature equilibrated receptor medium. Volumes collected weremeasured and recorded. Each test formulation was tested simultaneouslyin a minimum of 6 diffusion cells.

Following the final receptor phase sample, the residual drug remainingon the surface of the skin was determined.

Receptor sample preparation: The analytical method used to measure PGE-1concentration was an indirect method in which PGE-1 concentration insamples was determined after derivatization of PGE-1 into PGB (PGB beinga more stable molecule than PGE-1). The derivatization process consistedof treating a 1 mL sample with 1 mL of 1N NaOH for 2 hours at 50° C.After 2 hours, the reaction was stopped by adding 100 μL of HPLC grade85% o-phosphoric acid to each sample. Receptor fluid samples were thenplaced into 2 mL HPLC vials and analyzed for PGB content.

Analytical methodology: Analytical determinations were made by highperformance liquid chromatography (HPLC) using an Agilent 1050 LC moduleequipped with a variable wavelength detector, column oven, in-linedegasser and autosampler. Details regarding HPLC conditions used for thePGB are described in a separate report. In all cases, the amount of PGBpresent in the samples was determined by measuring the PGB peak againsta 6-point minimum calibration curve.

Statistical methodology: The data were expressed as flux (μg/cm²/hour)units, cumulative amount absorbed (μg/cm²) and percentage of doseapplied versus time. All data represent the average of the n=6replicates for each experiment and associated standard error. Groupmeans were evaluated for statistical significance by two-tailed, pairedt-tests based on equal or unequal variance assumption as appropriateusing Excel® statistical package (Microsoft Inc.). No adjustment wasmade to the results for this report for multiple comparisons.

The data obtained from the above measurements is reported graphically inthe figures.

FIGS. 2A and 2B show graphs illustrating average flux (FIG. 2A) andcumulative delivery (FIG. 2B) of PGE, across human skin vs. time forformulation number 11 (identified as “Sample 26649-4”) in Table 1,against a clear gel control of 1% PGE, 5% SEPA-0009, 1% Klucel HP, 65.1%ethanol, and 27.9% water. FIGS. 3A and 3B show graphs illustratingaverage flux (FIG. 3A) and cumulative delivery (FIG. 3B) of PGE₁ acrosshuman skin vs. time for formulations 11 (identified as “Sample 26649-4”)and 13 (identified as “Sample 26656-2”) in Table 1, against a clear gelcontrol of 1% PGE1, 5% SEPA-0009, 1% Klucel HF, 65.1% ethanol, and 27.9%water. FIGS. 4A and 4B show graphs illustrating average flux (FIG. 4A)and cumulative delivery (FIG. 4B) of PGE₁ across human skin vs. time forformulations 11 (identified as “Sample 26649-4”), 13 (identified as“Sample 26656-2”) and 16 (identified as “Sample 26658-2”) in Table 1,against a clear gel control of 1% PGE 1, 5%. SEPA-0009, 1% Klucel HF,65.1% ethanol, and 27.9% water.

Having described specific embodiments of the present invention, it willbe understood that many modifications thereof will readily appear or maybe suggested to those skilled in the art, and it is intended thereforethat this invention is limited only by the spirit and scope of thefollowing claims.

1. A vanishing cream base composition suitable for topical application of an active agent to an animal or plant comprising: a. from about 20 to about 70 wt. % water, based on the total weight of cream base composition; b. at least about 10 wt. %, based on the total weight of cream base, of at least one alcohol; c. at least one polymeric thickening agent comprising a nitrogen containing acrylic unit; d. a penetration enhancing effective amount of a skin penetration enhancing compound; and e. an emulsifying agent; wherein said cream base is stable upon storage at ambient conditions, and clarifies at a temperature greater than 30° C.
 2. A vanishing cream composition suitable for topical application of an active agent to an animal or plant comprising: a. from about 20 to about 70 wt. % water, based on the total weight of cream base composition; b. at least about 10 wt. %, based on the total weight of cream base, of at least one alcohol; c. at least one polymeric thickening agent comprising a nitrogen containing acrylic unit; d. a penetration enhancing effective amount of a skin penetration enhancing compound; e. an emulsifying agent; and f. an active agent; wherein said cream base is stable upon storage at ambient conditions, and clarifies at a temperature greater than 30° C.
 3. The composition of claim 2 wherein said emulsifying agent is polyoxyl 40 hydrogenated castor oil.
 4. The composition of claim 3 wherein said polyoxyl 40 hydrogenated castor oil is present in an amount from about 2 to about 17 wt. % based on total weight of the cream base composition.
 5. The composition of claim 2 having less than about 45 wt. % water.
 6. The composition of claim 2 having less than about 40 wt. % water.
 7. The composition of claim 2 having less than about 35 wt. % water.
 8. The composition of claim 2 wherein said at least one alcohol is present in at least about 35 wt. %.
 9. The composition of claim 2 wherein said at least one alcohol is present in at least about 40 wt. %.
 10. The composition of claim 2 wherein said at least one alcohol is present in at least about 45 wt. %.
 11. The composition of claim 2 wherein said at least one alcohol comprises ethanol.
 12. The composition of claim 2 wherein said polymeric thickening agent comprising a nitrogen containing acrylic unit is present in an amount from about 0.2 to about 10 wt. %, relative to the total weight of the cream base composition.
 13. The composition of claim 2 wherein said polymeric thickening agent comprising a nitrogen containing acrylic unit is present in an amount from about 3 to about 7 wt. %, relative to the total weight of the cream base composition.
 14. The composition of claim 2 wherein said polymeric thickening agent comprising a nitrogen containing acrylic unit is present in an amount from about 4 to about 6 wt. %, relative to the total weight of the cream base composition.
 15. The composition of claim 2 further comprising Germaben II-E.
 16. The composition of claim 2 wherein said skin penetration enhancing compound is a 1,3-dioxane, 1,3-dioxolane or acetal substituted with a C₆ to C₁₂-hydrocaryl group.
 17. The composition of claim 16 wherein said skin penetration enhancing compound is 2-n-nonyl-1,3-dioxolane.
 18. The composition of claim 17 wherein said 2-n-nonyl-1,3-dioxolane is present in an amount from about 5 to about 20 wt. %, relative to the total weight of the cream base composition.
 19. The composition of claim 17 wherein said 2-n-nonyl-1,3-dioxolane is present in an amount from about 7 to about 15 wt. %, relative to the total weight of the cream base composition.
 20. The composition of claim 2 wherein said thickener is an ammonium acryloyldimethlaurate-beheneth-25 methacrylate crosspolymer. 21-45. (canceled) 